Dh. Ko et al., NEW ANTIINFLAMMATORY STEROIDS - [16-ALPHA,17-ALPHA-D]-3'-HYDROXYIMINOFORMYL ISOXAZOLINE DERIVATIVES OF PREDNISOLONE AND 9-ALPHA-FLUOROPREDNISOLONE, Medicinal chemistry research, 7(5), 1997, pp. 313-323
In a continuing effort to increase the local to systemic activity rati
o (L/S) of antiinflammatory agents, a series of new steroids, 11 beta,
21-dihydroxy-3,20-dioxo-1,4-pregnadieno [16 alpha, 17 alpha-d]-3'-hydr
oxyiminoformyl isoxazoline (4a), 9 alpha-fluoro-11 beta,21-dihydroxy-3
,20-dioxo-1 ,4-pregnadieno[16 alpha, 17 alpha-d]-3'-hydroxyiminoformyl
isoxazoline (5a), and their 21-acetate derivatives, 4b and 5b, were s
ynthesized and evaluated. The topical anti-inflammatory activities of
these steroidal drugs were assessed in the croton oil-induced ear edem
a bioassay. In the ear edema bioassay, all compounds resulted in dose-
dependent inhibition of edema. From these dose-response profiles, the
following ED50 values were calculated: 230, 73, 251 and 88 mu g for pr
ednisolone (P), 4b, 5a and 5b, respectively. Calculated relative poten
cies, setting hydrocortisone (HC) = 1.0, were P, 2.2; 4b, 8.6; 5a, 2.6
and 5b, 7.4. All the new compounds displayed a higher local to system
ic activity ratio than P. Results of the five day rat croton oil ear e
dema bioassay indicated that only the parent compound P displayed sign
ificant suppressive effects on normal body weight gain, corticosterone
levels, adrenal and thymus weights. No significant suppressive effect
s were observed for any of the new compounds. Results obtained from th
is study suggest that the fusion of 3'-hydroxyiminoformyl isoxazoline
ring to the C-16/C-17 positions and fluorination at the 9 alpha-positi
on of the corticosteroid molecule enhance topical antiinflammatory act
ivity without inducing significant adverse systemic effects.